Optimized s-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models

James A. D. Good, Fang Wang, Oliver Rath, Hung Yi Kristal Kaan, Sandeep K. Talapatra, Dawid Podgorski, Simon P. MacKay, Frank Kozielski

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K-i(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacolcinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

LanguageEnglish
Pages1878-1893
Number of pages16
JournalJournal of Medicinal Chemistry
Volume56
Issue number5
Early online date11 Feb 2013
DOIs
Publication statusPublished - 14 Mar 2013

Fingerprint

Kinesin
3-tritylthio-L-alanine
Heterografts
Cysteine
Lung Neoplasms
Spindle Apparatus
Hematologic Neoplasms
Combination Drug Therapy
Nude Mice
Pharmaceutical Preparations
Biological Availability
Neoplasms
Proteins
Drug Therapy
Cell Line
Enzymes
ispinesib
SB 743921
Therapeutics

Keywords

  • optimized
  • s-trityl-L-cysteine-based inhibitors
  • kinesin spindle protein
  • potent in vivo
  • antitumor activity
  • lung cancer
  • xenograft models

Cite this

Good, James A. D. ; Wang, Fang ; Rath, Oliver ; Kaan, Hung Yi Kristal ; Talapatra, Sandeep K. ; Podgorski, Dawid ; MacKay, Simon P. ; Kozielski, Frank. / Optimized s-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 5. pp. 1878-1893.
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Optimized s-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models. / Good, James A. D.; Wang, Fang; Rath, Oliver; Kaan, Hung Yi Kristal; Talapatra, Sandeep K.; Podgorski, Dawid; MacKay, Simon P.; Kozielski, Frank.

In: Journal of Medicinal Chemistry, Vol. 56, No. 5, 14.03.2013, p. 1878-1893.

Research output: Contribution to journalArticle

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AU - Good, James A. D.

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